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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1914.)
© 2006 American Heart Association, Inc.

Thrombosis

Joint Linkage and Association of Six Single-Nucleotide Polymorphisms in the Factor XIII-A Subunit Gene Point to V34L As the Main Functional Locus

Marlies de Lange; Toby Andrew; Harold Snieder; Dongliang Ge; T. Simon Futers; Kristina Standeven; Tim D. Spector; Peter J. Grant; Robert A.S. Ariëns

From the Twin Research & Genetic Epidemiology Unit (M.d.L., T.A., H.S., T.D.S.), St Thomas’ Hospital, London, UK; Department of Biological Psychology (M.d.L.), Vrije Universiteit, Amsterdam, The Netherlands; Georgia Prevention Institute (H.S., D.G.), Department of Pediatrics, Medical College Georgia, Augusta; and Academic Unit of Molecular Vascular Medicine (T.S.F., K.S., P.J.G., R.A.S.A.), The Leeds Institute for Genetics, Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, UK.

Correspondence to Robert Ariëns, PhD, Academic Unit of Molecular Vascular Medicine, LIGHT Laboratories, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK. E-mail r.a.s.ariens{at}leeds.ac.uk

Objective— Activated factor XIII (FXIII) crosslinks fibrin to enhance the mechanical strength of a blood clot and increase its resistance to fibrinolysis. The prevalence of a common variant in the FXIII-A gene (V34L) has been reported to be lower in patients with myocardial infarction and ischemic stroke than in controls, suggesting a protective role for this polymorphism in vascular diseases. The current study investigated 6 single-nucleotide polymorphisms (SNPs) within the FXIII A-subunit gene to locate functional polymorphism(s) responsible for variation in FXIII activation.

Methods and Results— A total of 201 dizygotic twin pairs were genotyped for 1 promoter and all common nonsynonymous coding polymorphisms in the FXIII A-subunit gene: –246G>A, V34L, Y204F, P564L, V650I, and E651Q. Tests of linkage, association, and combined linkage and association were performed using QTDT software. Significant linkage to the V34L polymorphism (P=5x10^–12) as well as association (P=3x10^–49) was observed. Adjusting for association while performing linkage made the linkage signal disappear for the V34L polymorphism (from ²=47.55, P=5x10^–12 to ²=1.30, P=0.25). Only haplotypes containing the 34L allele showed association with FXIII activation.

Conclusion— Testing multiple SNPs in the FXIII A-subunit gene indicates that V34L is the main functional polymorphism influencing FXIII activation.

A joint test of linkage and association of 6 single-nucleotide polymorphisms in the factor XIII-A subunit gene, genotyped in 201 dizygotic female white twin pairs, indicates that a common variant (V34L) in the factor XIII-A subunit gene is the main functional variant influencing factor XIII activation.

Key Words: joint linkage and association analysis • functional locus • FXIIIV34L • FXIII activation • twins